Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients

Won Young Tak; Baek Yeol Ryoo; Ho Yeong Lim; Do Young Kim; Takuji Okusaka; Masafumi Ikeda; Hisashi Hidaka; Jong Eun Yeon; Eishiro Mizukoshi; Manabu Morimoto; Myung Ah Lee; Kohichiroh Yasui; Yasunori Kawaguchi; Jeong Heo; Sojiro Morita; Tae You Kim; Junji Furuse; Kazuhiro Katayama; Takeshi Aramaki; Rina Hara; Takuya Kimura; Osamu Nakamura; Masatoshi Kudo

doi:10.1007/s10637-018-0658-x

Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients

Won Young Tak, Baek Yeol Ryoo, Ho Yeong Lim, Do Young Kim, Takuji Okusaka, Masafumi Ikeda, Hisashi Hidaka, Jong Eun Yeon, Eishiro Mizukoshi, Manabu Morimoto, Myung Ah Lee, Kohichiroh Yasui, Yasunori Kawaguchi, Jeong Heo, Sojiro Morita, Tae You Kim, Junji Furuse, Kazuhiro Katayama, Takeshi Aramaki, Rina HaraTakuya Kimura, Osamu Nakamura, Masatoshi Kudo

Research output: Contribution to journal › Article › peer-review

39 Citations (Scopus)

Abstract

Purpose: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). Experimental design: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Results: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 10³/mm³). Conclusions: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.

Original language	English
Pages (from-to)	1072-1084
Number of pages	13
Journal	Investigational New Drugs
Volume	36
Issue number	6
DOIs	https://doi.org/10.1007/s10637-018-0658-x
Publication status	Published - 2018 Dec 1

Bibliographical note

Funding Information:
Conflict of interest Won Young Tak has served as a compensated consultant/advisor for Bayer HealthCare Pharmaceuticals Inc., Gilead Science Korea Ltd., AbbVie Ltd., Ono Pharma Korea Co., Ltd., Eisai Korea Inc., and Bukwang Pharmaceutical Co., Ltd. He has also received research grant support from Samil Pharm Co., Ltd. as well as honoraria from Bayer Korea Ltd., MSD Korea Ltd., Gilead Science Korea Ltd., AbbVie Ltd., Samil Pharm Co., Ltd., and Yuhan Co., Ltd.

Funding Information:
Masatoshi Kudo has received honoraria from Bayer, Eisai, MSD, and Ajinomoto. He has served as a compensated consultant/advisor for Bayer, Eisai, Kowa, MSD, BMS, Chugai, and Taiho. Furthermore, he has received research grant support from Daiichi Sankyo, Medico’s Hirata, Otsuka, Taiho, Astellas Pharma, Chugai, Abbvie, Bristol-Myers Squibb, Takeda, MSD, Eisai, Sumitomo Dainippon, and Bayer.

Funding Information:
This study was supported by Yakult Honsha Co., Ltd.

Funding Information:
Kazuhiro Katayama has received speaker’s bureau honorarium from Ajinomoto, Otsuka, Chugai, MSD, Bristol-Myers, Daiichi-Sankyo, Bayer, Nobelpharma Co., Ltd. He has also received research grant support from Bayer, Asuka, Kowa, and Bristol-Meyers.

Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

HDAC
Hepatocellular carcinoma
Resminostat
Sorafenib
Systemic chemotherapy

ASJC Scopus subject areas

Oncology
Pharmacology
Pharmacology (medical)

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10.1007/s10637-018-0658-x

Cite this

Tak, W. Y., Ryoo, B. Y., Lim, H. Y., Kim, D. Y., Okusaka, T., Ikeda, M., Hidaka, H., Yeon, J. E., Mizukoshi, E., Morimoto, M., Lee, M. A., Yasui, K., Kawaguchi, Y., Heo, J., Morita, S., Kim, T. Y., Furuse, J., Katayama, K., Aramaki, T., ... Kudo, M. (2018). Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients. Investigational New Drugs, 36(6), 1072-1084. https://doi.org/10.1007/s10637-018-0658-x

Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients. / Tak, Won Young; Ryoo, Baek Yeol; Lim, Ho Yeong et al.
In: Investigational New Drugs, Vol. 36, No. 6, 01.12.2018, p. 1072-1084.

Research output: Contribution to journal › Article › peer-review

Tak, WY, Ryoo, BY, Lim, HY, Kim, DY, Okusaka, T, Ikeda, M, Hidaka, H, Yeon, JE, Mizukoshi, E, Morimoto, M, Lee, MA, Yasui, K, Kawaguchi, Y, Heo, J, Morita, S, Kim, TY, Furuse, J, Katayama, K, Aramaki, T, Hara, R, Kimura, T, Nakamura, O & Kudo, M 2018, 'Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients', Investigational New Drugs, vol. 36, no. 6, pp. 1072-1084. https://doi.org/10.1007/s10637-018-0658-x

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title = "Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients",

abstract = "Purpose: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). Experimental design: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Results: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). Conclusions: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.",

keywords = "HDAC, Hepatocellular carcinoma, Resminostat, Sorafenib, Systemic chemotherapy",

author = "Tak, {Won Young} and Ryoo, {Baek Yeol} and Lim, {Ho Yeong} and Kim, {Do Young} and Takuji Okusaka and Masafumi Ikeda and Hisashi Hidaka and Yeon, {Jong Eun} and Eishiro Mizukoshi and Manabu Morimoto and Lee, {Myung Ah} and Kohichiroh Yasui and Yasunori Kawaguchi and Jeong Heo and Sojiro Morita and Kim, {Tae You} and Junji Furuse and Kazuhiro Katayama and Takeshi Aramaki and Rina Hara and Takuya Kimura and Osamu Nakamura and Masatoshi Kudo",

note = "Funding Information: Conflict of interest Won Young Tak has served as a compensated consultant/advisor for Bayer HealthCare Pharmaceuticals Inc., Gilead Science Korea Ltd., AbbVie Ltd., Ono Pharma Korea Co., Ltd., Eisai Korea Inc., and Bukwang Pharmaceutical Co., Ltd. He has also received research grant support from Samil Pharm Co., Ltd. as well as honoraria from Bayer Korea Ltd., MSD Korea Ltd., Gilead Science Korea Ltd., AbbVie Ltd., Samil Pharm Co., Ltd., and Yuhan Co., Ltd. Funding Information: Masatoshi Kudo has received honoraria from Bayer, Eisai, MSD, and Ajinomoto. He has served as a compensated consultant/advisor for Bayer, Eisai, Kowa, MSD, BMS, Chugai, and Taiho. Furthermore, he has received research grant support from Daiichi Sankyo, Medico{\textquoteright}s Hirata, Otsuka, Taiho, Astellas Pharma, Chugai, Abbvie, Bristol-Myers Squibb, Takeda, MSD, Eisai, Sumitomo Dainippon, and Bayer. Funding Information: This study was supported by Yakult Honsha Co., Ltd. Funding Information: Kazuhiro Katayama has received speaker{\textquoteright}s bureau honorarium from Ajinomoto, Otsuka, Chugai, MSD, Bristol-Myers, Daiichi-Sankyo, Bayer, Nobelpharma Co., Ltd. He has also received research grant support from Bayer, Asuka, Kowa, and Bristol-Meyers. Publisher Copyright: {\textcopyright} 2018, Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2018",

month = dec,

day = "1",

doi = "10.1007/s10637-018-0658-x",

language = "English",

volume = "36",

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T1 - Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients

AU - Tak, Won Young

AU - Ryoo, Baek Yeol

AU - Lim, Ho Yeong

AU - Kim, Do Young

AU - Okusaka, Takuji

AU - Ikeda, Masafumi

AU - Hidaka, Hisashi

AU - Yeon, Jong Eun

AU - Mizukoshi, Eishiro

AU - Morimoto, Manabu

AU - Lee, Myung Ah

AU - Yasui, Kohichiroh

AU - Kawaguchi, Yasunori

AU - Heo, Jeong

AU - Morita, Sojiro

AU - Kim, Tae You

AU - Furuse, Junji

AU - Katayama, Kazuhiro

AU - Aramaki, Takeshi

AU - Hara, Rina

AU - Kimura, Takuya

AU - Nakamura, Osamu

AU - Kudo, Masatoshi

N1 - Funding Information: Conflict of interest Won Young Tak has served as a compensated consultant/advisor for Bayer HealthCare Pharmaceuticals Inc., Gilead Science Korea Ltd., AbbVie Ltd., Ono Pharma Korea Co., Ltd., Eisai Korea Inc., and Bukwang Pharmaceutical Co., Ltd. He has also received research grant support from Samil Pharm Co., Ltd. as well as honoraria from Bayer Korea Ltd., MSD Korea Ltd., Gilead Science Korea Ltd., AbbVie Ltd., Samil Pharm Co., Ltd., and Yuhan Co., Ltd. Funding Information: Masatoshi Kudo has received honoraria from Bayer, Eisai, MSD, and Ajinomoto. He has served as a compensated consultant/advisor for Bayer, Eisai, Kowa, MSD, BMS, Chugai, and Taiho. Furthermore, he has received research grant support from Daiichi Sankyo, Medico’s Hirata, Otsuka, Taiho, Astellas Pharma, Chugai, Abbvie, Bristol-Myers Squibb, Takeda, MSD, Eisai, Sumitomo Dainippon, and Bayer. Funding Information: This study was supported by Yakult Honsha Co., Ltd. Funding Information: Kazuhiro Katayama has received speaker’s bureau honorarium from Ajinomoto, Otsuka, Chugai, MSD, Bristol-Myers, Daiichi-Sankyo, Bayer, Nobelpharma Co., Ltd. He has also received research grant support from Bayer, Asuka, Kowa, and Bristol-Meyers. Publisher Copyright: © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Purpose: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). Experimental design: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Results: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). Conclusions: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.

AB - Purpose: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). Experimental design: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Results: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). Conclusions: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.

KW - HDAC

KW - Hepatocellular carcinoma

KW - Resminostat

KW - Sorafenib

KW - Systemic chemotherapy

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Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients

Abstract

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